1. Field of the Invention
The present invention relates to oral lipid medicinal compositions, which improve the absorption of active ingredients, which are not adequately bio-available on oral administration, and methods for preparing such compositions.
2. Discussion of the Invention
It is well known that on oral administration of oral drugs, that have been available to date, numerous drugs cannot be adequately absorbed. Among others, such drugs include various antibiotics and in particular drugs with a peptide or protein structure. To date, the latter can be effectively applied only parenterally, since following oral administration, they become biochemically inactive already in the gastrointestinal tract, before they even reach the site of absorption. The best known example is the blood sugar reducing proteohormone, insulin.
Especially in the case of rectal and dermal applications, it is well known that carrier substrates, which contain, among other things, different mixtures of lipids, can lead to significant differences in drug absorption. Lipid mixtures of this kind have, as a function of the kind and proportion of added lipids (i.e., esters of glycerin and short, medium, or long chain, saturated or unsaturated fatty acids, which in turn can also be present as monoacylglycerides and monoacidic or mixed acid di- and triacylglycerides), a corresponding different solubility behavior and also different solubility behavior for the active ingredients. Consequently, quantitative and qualitative different relations of lipid mixtures can have a significant impact on drug absorption. In accordance with the resulting hydrophilic/lipophilic ratios, the active ingredients must also be worked into the lipid compounds in a specific pharmaceutical format.
However, rectal and dermal applications do not fulfill the prerequisites of fast bio-availability in all cases, as desired or required by some drugs, due to their specific pharmacokinetic profiles and anatomical peculiarities. Tests to apply oral formulations based exclusively on fats, in particular with triacylglycerides as tablets, compressed fat granules or smaller fat globules (fat pellets) with high melting points in order to attain delayed release through diffusion or enzymatic erosion, have already been known for a long time. However, these formulations require a specific manufacturing technology, are suitable primarily only for lipophilic drugs and exhibit no advantages in bio-availability with respect to the usual oral drug formulations, e.g., hydrophilic tablets. Therefore, they have not found any wide therapeutic use.
Attempts to use so-called liposomes, i.e., preferably with the use of phospholipids, such as, among others, phosphatidylcholine, manufactured smallest spherical lipid particles (nano particles), as a drug-including vehicle, are also known. The manufacture of these particles is technically complicated, and in particular liposomes have significant stability problems.
A commercial alternative is the attempt in the direction of highly disperse particles, containing primarily triacylglyceride particles (micro pellets), which are also present, e.g., as a powder.
Another problem with different fat mixtures is that they can exhibit unstable modifications and thus are sensitive to storage. This applies in particular to fat mixtures, e.g., based on cacao butter. The use of unsaturated fatty acids, such as oleic acid (C18:1), linoleic acid (C18:2) and linolenic acid (C18:3) in fat mixtures can also result in oxidation-induced storage problems with the risk of rancidity. Long chain triacylglycerides also have relatively poor solution and solubility properties and are, therefore, suitable primarily for more lipophilic drugs. In addition, apparently following absorption, they are also transported predominantly over lymphatic paths in the gastrointestines, which is a different pathway for the transport of esters of glycerin and short chain fatty acids. Due to the distinctly lower flux rates in the lymph pathways, this results on the whole in slower absorption. In addition, long chain triacylglycerides of gastrointestinal lipases are hydrolyzed more than medium chain ones.
Thus, there remains a need for improving the absorption of active ingredients, which are not adequately bio-available following oral administration.